Several markers identify cancer stem cell-like (CSC) populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. The endothelial protein C receptor (EPCR) is a stem cell marker in hematopoietic, neuronal and epithelial cells. We recently demonstrated that EPCR is crucial for tumor growth in the mammary gland using a transgenic mouse mammary tumor model as well as a xenograft model for human triple-negative breast cancer. Furthermore, we analyzed gene expression patterns and found that EPCR+ cells upregulate gene clusters associated with the CSC phenotype. EPCR+ cells are also uniquely able to form mammospheres in cell culture. Interestingly, in the human breast cancer cell line that we studied, the EPCR+ subpopulation appears to exist in equilibrium with another subpopulation characterized by a distinct set of stem cell and progression markers, expression of the cell surface receptor tissue factor (TF) and lack of EPCR expression. Indeed, we found that in vitro these cells coexist as relatively stable subpopulations. In vivo only EPCR+/TFlow cells are highly tumorigenic when transplanted into mice. However in growing tumors the equilibrium of EPCR+ and EPCR- cells is restored. Finally we showed that a monoclonal antibody (mAb) against EPCR that blocks ligand-binding to EPCR was superior to a non-function-blocking anti-EPCR mAb in inhibiting tumor growth in a breast cancer xenograft model. Based on these preliminary results we propose here to further test the hypothesis that EPCR is a CSC marker in breast cancer and to explore EPCR function breast cancer progression. We plan to investigate the generality of our findings using additional human breast cancer cell lines, to extend our study from mammary tumors to metastasis, to examine EPCR expression in human breast cancer tissues and test the effect of anti-EPCR alone and combined with anti-TF on preclinical models of breast cancer metastasis.